Vertebrata have developed myelinated nerve to enable high speed processing of a large amount of information. The myelin sheath, which is characteristic of the myelinated nerve, is formed upon enveloping of nerve axon by cytoplasmic membrane of oligodendrocyte or Schwann cell, and has a multilayer structure. As a result, the nerve becomes insulated as well as acquires an extremely high impedance and extremely low capacitance. The sodium channels are present in accumulation in the nodes of Ranvier, which is a cut line between a myelin sheath and another myelin sheath, and facilitate saltatory conduction of an impulse and enable high speed processing of information (namely, high nerve conduction velocity).
The main component forming the myelin sheath is myelin and, as a component to stabilize the multilayer structure of the myelin sheath, myelin specific proteins are known. Of these, proteolipid protein and P0 protein are involved in crosslinking and adhesion between myelin membranes, and myelin basic protein (hereinafter to be referred to as MBP) is present in the cytoplasm of myelin sheath and involved in compaction of the sheath (Morell P. et al., in Basic Neurochemistry, Siegel G J et al. Eds. Ravan Press, p. 117–143 (1994)). In addition, myelin-associated glycoprotein (hereinafter sometimes to be referred to as MAG) is involved in adhesion between axon and myelin sheath (Quarles R H, Myelin-associated glycoprotein: functional and clinical aspects, in Neuronal and Glial Proteins: Structure, Function and Clinical Application, Marangos P J et al. Eds. Academic Press, New York, p. 295 (1988)).
The MAG belongs to the immunoglobulin superfamily and the electrophoretic mobility is 100-kDa. When myelination is started, MAG is expressed by the oligodendrocyte in the central nervous system and by Schwann cell in the peripheral nervous system. The proportion of MAG in myelin is only 1% in the central nervous system and 0.1% in the peripheral nervous system. Recently, it has been clarified that MAG plays not only a role as a simple adhesion molecule but is also positively involved in the formation and maintenance of myelin sheath, as mentioned below.
In Schwann cell, where MAG is excessively expressed in vitro, myelination is promoted (Owens G C et al., J. Cell Biol., 111, p. 1171–1182 (1990)), but in Schwann cell, where expression of MAG is decreased, myelination is suppressed (Owens G C et al., Neuron, 7, p. 565–575 (1991)). In vivo, the number of myelinated nerves of MAG deficient mice decreases and the number of unmyelinated nerve increases, which is considered to be caused by a retardation in the myelin formation (Bartsch S. et al., Brain Res. 762, p. 231–234 (1997)). On the other hand, there is also a report documenting that, despite a morphological abnormality observed in the periaxonal space between axon and myelin sheath, no difference is found in the number of myelinated nerves, thickness of myelin sheath or the diameter of axon, of the normal mice and MAG deficient mice (Li C. et al. Nature, 369, p. 747–750 (1994)). Therefore, many points remain unknown about the relationship between MAG and myelination.
As regards the molecular mechanism of myelination, there is only a report at present that MAG binds with an axon receptor to activate Fyn tyrosine kinase (Umemori H. et al., Nature, 367, p. 572–576 (1994)), and then promotes expression of MBP gene (Umemori H., J. Neurosci., 19, p. 1393–1397 (1999)), which is not sufficient to clarify the mechanism.
As the diseases mainly presenting hypomyelination, and further, dysmyelination or demyelination, multiple sclerosis, encephalitis, myelitis, Guillain-Barrè syndrome, chronic inflammatory demyelinating polyradiculitis, heavy metal toxicosis, diphtheria toxicosis, hypothyroidism, metachromatic leukodegeneration, Charcot-Marie-Tooth disease and the like are known (Takeshi Yasuda et al., Clinical Test, 40, p. 760–766 (1996)).
These diseases are reported to be treated with interferon, steroid, γ-globulin, plasma exchange or immunosuppressant (Gen Sobue, Brain and Development, 30, p. 115–120 (1998), Hajime Harukawa et al., Nippon Rinsho, 55, p. 187–194 (1997)), but the situation is not entirely satisfactory. Since in patients with multiple sclerosis, disappearance of MAG in the early stages of onset of the disease is observed (Moller J R, Ann. Neurol., 22, p. 469–474 (1987)), a drug that promotes expression of MAG is expected to be effective for the prophylaxis and/or treatment of the onset of the above-mentioned diseases.
In JP-A-60-34952, JP-B-64-7074, JP-B-3-16348, JP-B-4-15781, JP-B-4-15782, JP-B-5-29031, JP-B-5-41143 and JP-B-5-74589, the compound of the formula (I) to be mentioned below is disclosed, which is useful for the prophylaxis and treatment of thrombosis, stroke, myocardial infarction, sudden cardiac death, angina pectoris, hypertension, asthma, nephritis and the like, optically active forms thereof and pharmaceutically acceptable salts thereof having a pharmacological action, such as potent TXA2 biosynthesis inhibitory action, platelet aggregation inhibitory action and vasodilating action and the like. WO97/24333 discloses that, of these compounds, 4-[α-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3,5-dimethylbenzoic acid, optically active forms thereof and pharmaceutically acceptable salts thereof are useful agents for the prophylaxis and/or treatment of diabetic complications.
However, it is not described or suggested that a compound of the formula (I) to be mentioned later has an action to promote expression of MAG.
It is an object of the present invention to provide MAG expression promoters. More particularly, an object of the present invention is to provide MAG expression promoters that can be an agent for the prophylaxis and/or treatment of diseases mainly presenting hypomyelination, and further, dysmyelination or demyelination.